Characterization of a Citrulline 4‐Hydroxylase from Nonribosomal Peptide GE81112 Biosynthesis and Engineering of Its Substrate Specificity for the Chemoenzymatic Synthesis of Enduracididine
| Autor: | Hans Renata, Christian R. Zwick, Max B. Sosa |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
chemistry.chemical_classification
Dipeptide 010405 organic chemistry Chemistry Sequence alignment General Chemistry Protein engineering General Medicine 010402 general chemistry 01 natural sciences Catalysis 0104 chemical sciences Amino acid chemistry.chemical_compound Enzyme Biosynthesis Biochemistry Nonribosomal peptide Prokaryotic translation |
| Zdroj: | Angewandte Chemie. 131:19030-19034 |
| ISSN: | 1521-3757 0044-8249 |
| Popis: | The GE81112 tetrapeptides are a small family of unusual nonribosomal peptide congeners with potent inhibitory activity against prokaryotic translation initiation. With the exception of the 3-hydroxy-l-pipecolic acid unit, little is known about the biosynthetic origins of the non-proteinogenic amino acid monomers of the natural product family. Here, we elucidate the biogenesis of the 4-hydroxy-l-citrulline unit and establish the role of an iron- and α-ketoglutarate-dependent enzyme (Fe/αKG) in the pathway. Homology modelling and sequence alignment analysis further facilitate the rational engineering of this enzyme to become a specific 4-arginine hydroxylase. We subsequently demonstrate the utility of this engineered enzyme in the synthesis of a dipeptide fragment of the antibiotic enduracidin. This work highlights the value of applying a bioinformatics-guided approach in the discovery of novel enzymes and engineering of new catalytic activity into existing ones. |
| Databáze: | OpenAIRE |
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